Multifaceted response of microglia in the cuprizone model of demyelination

The cuprizone diet paradigm, which involves selective depletion of oligodendrocytes and subsequent myelin loss, provides an excellent model to study the neuroimmune response to demyelination and remyelination. Microglia, the resident immune cells of the central nervous system, mount a robust response to cuprizone administration. However, the specific triggers and temporal trajectory of microglia activation are not well-defined. Moreover, it is unclear the extent to which microglia respond to cuprizone directly rather than to cuprizone-induced demyelination. In this study, we characterized the temporal dynamics of microglial activation in the corpus callosum during the early and peak phases of demyelination and during early remyelination following cuprizone withdrawal. Microglia number and area showed a dramatic increase by 1 week (early phase) and persisted throughout 4 weeks (peak phase), with partial recovery during early remyelination. The early demyelination phase was marked by morphological remodeling of microglia and engulfment of degraded myelin. This timepoint correlated with increased expression of Mertk and Apoe, and a concurrent decrease in the proinflammatory response genes, Tnf and Ifnb1. These findings indicate that the early neuroimmune response to cuprizone-induced demyelination is marked by an augmented phagocytic response accompanied by downregulation in inflammatory signaling. In the retina, which is devoid of oligodendrocytes or myelin, microglia did not display morphological alterations and instead downregulated CD68 expression in response to cuprizone administration. Our novel findings reveal that in addition to the microglial response to cuprizone-induced demyelination, cuprizone exerts direct effects on microglia even in absence of in vivo demyelination.